Medicinal agents useful in the treatment of vestibular disorders or relieving symptoms of vestibular disorders, such as histamine, are known to act via the histaminergic system. Histamine is a potent bioactive substance that has been studied for nearly a century, acting as an aminergic neurotransmitter in the nervous system and as a local mediator in the gut, skin, and immune system peripherally and in the brain. Betahistine is a structural analog of histamine with similar pharmacologic properties, but without potentially severe side effects of histamine such as anaphylactic reactions.
Betahistine is known to have therapeutic benefits in the treatment of vestibular vertigo, e.g. in benign paroxysmal positional vertigo, vestibular neuritis, or Meniere's disease. The therapeutic effects of betahistine in Meniere's disease, a condition characterized by vertigo, tinnitus, hearing loss and the sensation of pressure or pain in the affected ear, have been evaluated in a large number of clinical trials. However, the results of the trials are controversial and the general opinion of the reviewers is that there is still insufficient evidence to say whether betahistine has any effect on Meniere's disease or not. Betahistine is also known to have therapeutic benefits in vestibular rehabilitation, e.g., significantly shortened time to recovery for postural stability and subjective visual vertical and head orientation in Meniere's patients following vestibular neurectomy.
Betahistine is also known to have therapeutic effects in the treatment of neurological disorders such as obesity, attention deficit hyperactivity disorder, cerebrovascular disease/dementia, narcolepsy/sleep disorders, Parkinson, addiction, schizophrenia, Gilles de la Tourette syndrome, or Alzheimer's disease.
In humans, betahistine is usually administered orally in the form of tablets or a solution, usually two to three times daily, up to 6 times a day. Betahistine is known for its short plasma half-life (3-4 h) which necessitates frequent administration and may lead to noncompliance, especially in elderly patients. In addition, after oral administration, betahistine is readily and almost completely absorbed from all parts of the gastro-intestinal tract. Following absorption, the drug is rapidly and almost completely metabolized into 2-pyridylacetic acid (2-PAA; which has no pharmacological activity) by monoamine oxidase. Due to its very high first pass metabolism, the absolute bioavailability of orally administered betahistine is estimated to be around 1% (SmPC). Accordingly, plasma levels of betahistine are very low.
Thus, the strong first-past effect following oral administration of betahistine limits the compound's efficacy in clinical practice, and substantially higher doses may indeed be necessary in order to achieve more pronounced results. Therefore, there is a need to provide improved pharmaceutical compositions comprising betahistine, and methods of administration thereof for the treatment of otological or neurological disorders, including inner ear dysfunctions, which provides increased efficacy and allows for a reduced frequency and/or daily dosage, as well as to attain a more rapid and prolonged effect.